Autoimmune disease and risk of postpartum venous thromboembolism

Background The risk of pregnancy-related mortality in the United States has nearly doubled since 1990, with venous thromboembolism (VTE) accounting for approximately 10% of these deaths. Objectives The objective of this study was to assess whether preexisting autoimmune disease is a risk factor for postpartum VTE. Methods Using the MarketScan Commercial and Medicare Supplemental administrative databases, a retrospective cohort study analyzed whether postpartum persons with autoimmune disease had a higher risk of postpartum VTE incidence than postpartum persons without autoimmune disease. Using International Classification of Diseases codes, we identified 757,303 individuals of childbearing age who had a valid delivery date with at least 12 weeks of follow-up. Results Individuals were, on average, 30.7 years old (SD, 5.4), and 3.7% (N = 27,997 of 757,303) of them had evidence of preexisting autoimmune disease. In covariate-adjusted models, postpartum persons with preexisting autoimmune disease had higher rates of postpartum VTE than postpartum persons without autoimmune disease (hazard ratio [HR], 1.33; 95% CI, 1.07-1.64). When analyzed by individual autoimmune disease, those with systemic lupus erythematosus (HR, 2.49; 95% CI, 1.47-4.21) and Crohn’s disease (HR, 2.49; 95% CI, 1.34-4.64) were at an elevated risk of postpartum VTE compared with those without autoimmune disease. Conclusion Autoimmune disease was associated with a higher rate of postpartum VTE, with evidence that the association was most pronounced among individuals with systemic lupus erythematosus and Crohn’s disease. These findings suggest that postpartum persons of childbearing age with autoimmune disease may require more monitoring and prophylactic care after delivery to prevent potentially fatal VTE events.


| I N T R O D U C T I O N
The risk of pregnancy-related mortality has nearly doubled in the United States in the past 30 years, with 20.1 deaths per 100,000 live births reported in 2019 [1,2]. Venous thromboembolism (VTE), which consists of both pulmonary embolism (PE) and deep vein thrombosis (DVT), occurs in approximately 120 of every 100,000 pregnancies [3,4]. PE is responsible for about 9% of pregnancy-associated deaths [1,5]. VTE risk is elevated in pregnancy because of an acquired procoagulant state, mechanical obstruction, and many other factors [6].
These factors increase the risk of VTE antepartum and during the puerperium [7,8]. In the puerperium, VTE risk is highest during the first week after delivery (90 per 100,000), declines to 25 per 100,000 in the second week, and is near the baseline levels by around the 12th week [9]. Factors such as smoking and obesity, as well as certain obstetric procedures and complications (eg, cesarean delivery, obstetrical hemorrhage, or preeclampsia), confer an increased risk for VTE [9][10][11]. For pregnant persons perceived to be at particularly high VTE risk, clinical practice guidelines from the American Hematologic Society and several obstetric societies recommend prophylactic measures such as administration of low-molecular-weight heparin during and after pregnancy [12][13][14][15]. Pregnancy-related VTE is a significant source of morbidity and mortality, and identification of novel risk factors for pregnancy-associated VTE remains a priority to appropriately target prophylactic measures and thus reduce complications due to pregnancy-associated VTE.
Several autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBDs), increase the risk of VTE in the nonpregnant population [16][17][18][19]. For example, patients with SLE have up to a 26% risk of experiencing a thrombosis event throughout their disease course [19,20]. These autoimmune diseases are believed to increase the VTE risk by upregulating the body's procoagulants while simultaneously decreasing the physiological anticoagulants by systemic inflammation.
A high prevalence of antiphospholipid antibodies is common in patients with autoimmune disease, leading to an increased risk of antiphospholipid antibody syndrome, which targets phospholipid-protein complexes that are known to increase the risk of VTE [20]. Given that pregnancy itself is a procoagulant state [8], autoimmune diseases may exacerbate the already increased risk during and immediately after pregnancy.
Few studies have estimated the association of autoimmune disease with the risk of pregnancy-associated VTE. A barrier to evaluating this association is the relative rarity of both conditions. To minimize this limitation, we constructed a retrospective cohort using data from a large administrative database composed of medical claims from the employer-provided health insurance. We tested whether the hypothesis that autoimmune disease is associated with an increased risk of VTE in the 12 weeks after delivery. We also evaluated the association of several specific autoimmune conditions with VTE risk, namely thyrotoxicosis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, RA, SLE, and Crohn's disease. Among these, we hypothesized that those that were systemic (eg, SLE) would be more strongly associated with postpartum VTE than those that are organ-specific autoimmune diseases (eg, thyrotoxicosis or Hashimoto's thyroiditis).

| Study design and study population
From MarketScan, we obtained records for a random sample of 1 million individuals with evidence of pregnancy. Using these enrollees, we identified 814,647 persons with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), or Tenth Essentials • Pregnancy and autoimmune diseases have inflammatory factors that increase the risk of blood clots.
• We tested whether autoimmune disease was associated with postpartum venous thromboembolism (VTE).
• Postpartum persons with autoimmune disease had a 33% increased risk of postpartum VTE.
• Postpartum persons with Crohn's disease and systemic lupus erythematosus had the highest VTE risk.
Revision (ICD-10-CM) diagnosis inpatient code for delivery. To be included as a delivery in this study, pregnancies had to last at least 20 weeks, indicated by International Classification of Diseases (ICD) codes covering natural delivery, Caesarian sections, or extraction by other methodologies (most codes in V27.xx and Z37.xx). Although the face validity of these codes is high, formal validation studies of ICD codes for all deliveries are lacking. However, validation exists for some specific delivery types, and the accuracy of the codes appears reasonable (eg, caesarian section delivery has 98% specificity and 73% sensitivity) [21,22]. The ICD-9/10 diagnosis and procedure codes used to classify delivery are compiled in Supplementary Table 1. After restricting to individuals of common childbearing age (15-45 years) with 3 months of continuous enrolment before their delivery date, we identified 757,303 persons who delivered for the analytic dataset.
Only the first birth in the 7-year follow-up period was considered for this analysis. The start of study follow-up was defined as the date of a pregnant person's first delivery.

| Exposure assessment
Twenty-four unique autoimmune diseases were considered for this analysis and are listed with their corresponding ICD-9/10-CM codes in Supplementary Table 2. The validity of ICD codes for identifying autoimmune disease varies by disease but is generally high [23,24].
For example, a systematic review reported ICD-9-CM code 710.0 to have a PPV of 70% to 90% for identifying SLE [23]. Preexisting autoimmune diseases were identified by the presence of 2 or more inpatient and/or 2 or more outpatient ICD codes occurring more than 7 days apart before the first delivery date. Owing to the low prevalence of several autoimmune diseases among persons of childbearing age, only 7 autoimmune diseases were considered for stratified analyses: thyrotoxicosis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, RA, SLE, and Crohn's disease.

| Outcome assessment
Postpartum VTE events were confined to cases occurring on the date of delivery and 12 weeks thereafter. Incident VTE events were identified by the presence of at least one inpatient ICD-9/10-CM diagnosis code or 2 outpatient diagnosis codes 7 to 185 days apart for VTE. We used an algorithm of ICD-9/10-CM codes and proof of anticoagulation treatment, which had been validated against medical record review, to detect VTE (PPV = 91%) [25]. Owing to the nature of this manuscript, we also added pregnancy-related ICD-9/10-CM codes to our algorithm (all codes are found in Supplementary   Table 3). Inpatient and outpatient diagnoses were confirmed with at least one anticoagulant prescription occurring within 31 days of the VTE date. Patients without an anticoagulant prescription were excluded from the analyses.

| Covariates
MarketScan demographic, inpatient, outpatient, and pharmacy claim data before the delivery date were used to assess the presence of relevant covariates. Comorbidities and prescription fills were assessed for any relevant ICD-9 or ICD-10 codes occurring at any time before the delivery date. We used ICD-9/10-CM coding algorithms developed by Quan to identify comorbidities [26]. These algorithms were found to outperform the existing comorbidity scores in administrative data [26].

| Statistical analysis
Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for the risk of postpartum VTE within 12 weeks of delivery, comparing postpartum persons with preexisting autoimmune disease with those without autoimmune diseases. Two adjusted models were used. Model 1 adjusted for age, hypertension, diabetes (both mellitus and gestational), preeclampsia, multiple gestation, and antepartum hemorrhage.
Model 2 included all comorbidities in Model 1 plus prescription variables (immunosuppressant drugs, dexamethasone, oral prednisone, or hydroxychloroquine). Identical analyses also investigated the risk of postpartum VTE within 0 to 6 weeks after delivery and 7 to 12 weeks after delivery to assess whether risk differed by time postpartum.
Associations were also evaluated separately for specific autoimmune diseases where enough VTE cases were available to derive meaningful estimates of association. All data management and analyses were performed using SAS version 9.4 (SAS Inc).

| R E S U L T S
The average age of postpartum persons in the analytic sample was

| SLE and postpartum VTE
Systemic autoimmune diseases, such as SLE, are associated with increased inflammation, potentially increasing molecular procoagulant factors that can eventually contribute to VTE [27]. Coupled with pregnancy-associated factors (eg, procoagulant state and stasis), systemic autoimmune diseases may increase the risk of VTE. In the present analysis of MarketScan data, postpartum persons with SLE were at a 2.5-fold greater risk of developing VTE. Patients with SLE have been shown to have an increased risk of VTE, in both general and peripartum populations [19]. A review by Zöller et al. [20] [30] showed that IBD patients have a 3-fold to 4-fold increased risk of developing a DVT (incidence rate ratio, 4.7; 95% CI, 3.5, 6.3) or PE (incidence rate ratio, 2.9; 95% CI, 1.8, 4.7). These findings are corroborated by several other studies, and effect estimates were often similar for the other IBDs, such as ulcerative colitis. For instance, a Danish study by Kappelman et al. [31] found that even young patients with IBD (ie, those aged 20 years and younger) were at an increased risk of VTE, despite their youth and VTE generally occurring at older ages [32]. Evidence of IBD and VTE risk in the peripartum period is somewhat limited. The HCUP-NIS study, which showed a higher risk of pregnancy-associated VTE with SLE, also reported an elevated risk among pregnant persons with Crohn's disease (OR, 2.71; 95% CI, 1.50, 4.90) [28]. To our knowledge, the only other study investigating IBD and peripartum VTE was a Danish study by Hansen et al. [33]. This study found that individuals with IBD, compared with those without, were at an elevated risk for postpartum VTE both during pregnancy (relative risk, 1.67; 95% CI, 1.15, 2.41) and in the postpartum period (relative risk, 2.10; 95% CI, 1.33, 3.30). The results were similar when the authors evaluated Crohn's disease, specifically.
In the present MarketScan analysis, Chron's disease was associated with a 2.5-fold increased risk of VTE. We were not able to evaluate ulcerative colitis specifically, owing to its rarity in our study population. Our findings enhance the existing literature suggesting that IBD, specifically Crohn's disease, is associated with an increased risk of VTE in the postpartum period.   [40]. We also found a null association among those with psoriasis; however, individuals with psoriasis may have been misclassified because of rashes such as eczema or contact dermatitis being coded as psoriasis. All autoimmune disease subclassifications included in this study population had less than 15 postpartum VTE events during the study period. As such, our findings for these autoimmune diseases must be viewed with caution owing to poor precision.

| VTE prophylaxis among peripartum persons with autoimmune disease
There is an overall low absolute risk for a pregnancy-related VTE; however, reducing pregnancy-associated VTE is a public health priority, given the potential for devastating consequences, and the observation that underserved and diverse populations are at an increased risk of VTE [41] and have higher a burden of autoimmune diseases [42][43][44]. Our findings, from a large real-world sample, provide additional support for the existing clinical practice guidelines from the American College of Obstetricians and Gynecologists, the

Society of Obstetricians and Gynecologists of Canada, and the Royal
College of Obstetricians and Gynecologists (summarized in Table 3)   in the analysis more than once, if they have multiple discharges [28].

| Strengths and limitations
MarketScan's inclusion of outpatient data allowed for a more comprehensive evaluation of patient history and establishing a clinically meaningful denominator, and the approach is that of a traditional cohort with each individual included in the analysis only once.
As another limitation, variables in this study were defined using ICD codes from the billing data and are subject to misclassification.
However, whenever possible, we used ICD-based definitions that were validated against a medical record review to minimize mis-

RELATIONSHIP DISCLOSURE
There are no competing interests to disclose.